The role of neuropeptide somatostatin in the brain and its application in treating neurological disorders

Abstract

Somatostatin (SST) is a well-known neuropeptide that is expressed throughout the brain. In the cortex, SST is expressed in a subset of GABAergic neurons and is known as a protein marker of inhibitory interneurons. Recent studies have identified the key functions of SST in modulating cortical circuits in the brain and cognitive function. Furthermore, reduced expression of SST is a hallmark of various neurological disorders, including Alzheimer's disease and depression. In this review, we summarize the current knowledge on SST expression and function in the brain. In particular, we describe the physiological roles of SST-positive interneurons in the cortex. We further describe the causal relationship between pathophysiological changes in SST function and various neurological disorders, such as Alzheimer's disease. Finally, we discuss potential treatments and possibility of novel drug developments for neurological disorders based on the current knowledge on the function of SST and SST analogs in the brain derived from experimental and clinical studies.

Fig. 1. Overview of the properties of SSTR family members: expression localization, binding affinity for SST and its analogs, and associations with neurological disorders.

Various subtypes of SSTRs are distributed differently across the central nervous system and the peripheral nervous system. Gray shades indicate the existence of the receptor subtypes in the corresponding area. Red shades indicate receptor subtypes with a strong binding affinity (IC₅₀ < 10 nM). Note that SST shows a high binding affinity for all SSTR subtypes. CST resembles SST and has a similar strong binding affinity for all SSTR subtypes. SST analogs have selective binding properties for certain subtypes of SSTRs and sometimes have higher affinity for SSTRs than SST. Alterations in SSTR expression levels are observed in the neurological disorders discussed in this paper. It is well known that the expression levels of SSTRs are altered in AD patients, whereas the SSTR expression level in other disorders is less clear.

Fig. 2. The expression of five types of SSTRs and SST family genes in excitatory and inhibitory neurons in the VISp and ALM.

a Mean gene expression (RPKM: reads per kilobase of transcript per million mapped reads) of SSTR1–5, CST, and SST in excitatory neurons (left column) and inhibitory neurons (right column) in the VISp. The data are from mouse single-cell RNA sequencing data from the Allen Brain Atlas (total 15,413 cells; version 2018). The bars represent the mean ± SEM. Genetic markers of the cortical layers were selected based on previous literature. Rasgrf2 Ras protein-specific guanine nucleotide releasing factor 2, Calb1 calbindin1, Rorb RAR-related orphan receptor B, Scnn1α sodium channel epithelial 1 subunit alpha, Rbp4 retinol-binding protein 4, Trib2 Tribbles pseudokinase 2, Ctgf connective tissue growth factor, Pvalb parvalbumin, Sst somatostatin, Vip vasoactive intestinal peptide, GAD glutamate decarboxylase. b Same as a, but for the ALM (total 10,068 cells). Cux2 was used as a genetic marker of layer 2/3 excitatory neurons instead of Calb1. Cux2 Cut-like homeobox 2.

Fig. 3. Schematic illustration of SST release in the presynaptic terminal of an SST⁺ IN.

In SST-expressing neurons, SST and GABA are known to be colocalized and coreleased. SST (yellow dots) and GABA (gray dots)-containing vesicles are first delivered to the presynaptic terminal and released in a calcium-dependent manner through exocytosis. It has been reported that more time and higher calcium levels are needed to release SST from SST⁺ neurons with higher activity than GABA, as SST is usually delivered in dense-core vesicles (yellow circles). Furthermore, glutamate (blue dots) released from nearby glutamatergic neurons can evoke the release of SST and GABA by activating AMPA/NMDA receptors on axon terminals. Released GABA can inhibit GABA release and SST release through activation of GABA_B autoreceptors and heteroreceptors, respectively. Released SST can bind to SSTR subtypes 1–5 expressed on postsynaptic neurons and then inhibit calcium influx. This eventually leads to the reduced excitability of postsynaptic neurons through a downstream signaling pathway.

Fig. 4. Decrease in SST expression in the brain in the context of various neurological disorders.

In the normal human brain (left), SST is highly expressed throughout the brain and in the cerebrospinal fluid. The most abundant SST isoform in the brain is SST-14, which contains 14 amino acids with a disulfide bond between cysteine residues. In the context of various neurological disorders (right), alterations in SST expression in a specific region or throughout the brain are observed. A decrease in SST expression might lead to a shrinkage of the brain and an imbalance in neural networks and function. The following disorders showing such pathologies are discussed in the text: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, major depressive disorder, and schizophrenia. Three approaches can be used to deliver functional neuropeptide SST to the brain for the treatment of these disorders: chemical modification to enhance BBB penetration, nanoformulations, and gene therapy techniques.